The goal of this translational project is to optimize targeted T-cells with chimeric antigen receptors (CARs) for use in mesothelioma. CARs are now beginning to show activity in a number of pilot clinical trials, however two issues have emerged that provide a barrier to rapid progress in the field: 1) available preclinical models have not accurately predicted the safety of CARs, and unexpected toxicities from cytokine release and tissue damage has been reported in recent trials; 2) high costs and long lead times required for vector production have slowed the clinical application of T cells expressing CARs, and prevent a facile and iterative approach to optimize CAR design and determine the optimal target structures on tumor cells. Our preliminary data establishes that T lymphocytes can be efficiently modified by mRNA electroporation without integration associated safety concerns, and that repeated infusions of